2Naturally Occurring Carcinogens and Anticarcinogens in the Diet

This chapter addresses two questions: (1) what is the current state of knowledge regarding the presence and availability of carcinogens and anticarcinogens in the human diet? and (2) how much do we know about the dietary factors that modify carcinogenesis?

Environmental exposures to naturally occurring chemicals occur principally from the food and water we consume (approximately 1-1.5 kg/day of each) and from inspired air (approximately 18 kg/day). While air and water frequently contain at least trace levels of contaminants of human origin, they are seldom a source of naturally occurring substances that raise health concerns, including those about cancer. Among the uncommon exceptions is arsenic. Although it occurs at a few parts per billion (ppb) in most drinking waters, it occurs at the part per million (ppm) level in spring, well, and surface waters in arsenic-rich areas in the United States and in many other countries (Underwood 1973, NRC 1977). Food, however,

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"2 Naturally Occurring Carcinogens and Anticarcinogens in the Diet."
Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances.
Washington, DC: The National Academies Press, 1996.

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2
Naturally Occurring Carcinogens and Anticarcinogens in the Diet
This chapter addresses two questions: (1) what is the current state of knowledge regarding the presence and availability of carcinogens and anticarcinogens in the human diet? and (2) how much do we know about the dietary factors that modify carcinogenesis?
Exposure To Naturally Occurring Chemicals
Naturally occurring chemicals present in our food supply can be classified into the following five categories: constitutive naturally occurring substances, derived naturally occurring substances, acquired naturally occurring substances, pass-through naturally occurring substances, and added naturally occurring substances. These are defined in Chapter 1.
Environmental exposures to naturally occurring chemicals occur principally from the food and water we consume (approximately 1-1.5 kg/day of each) and from inspired air (approximately 18 kg/day). While air and water frequently contain at least trace levels of contaminants of human origin, they are seldom a source of naturally occurring substances that raise health concerns, including those about cancer. Among the uncommon exceptions is arsenic. Although it occurs at a few parts per billion (ppb) in most drinking waters, it occurs at the part per million (ppm) level in spring, well, and surface waters in arsenic-rich areas in the United States and in many other countries (Underwood 1973, NRC 1977). Food, however,

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is overwhelmingly our major source of exposure to naturally occurring chemicals and is therefore the focus of this report.
The Composition of Foods
Food, of course, is simply what we choose to eat, a choice heavily influenced by availability and culture (Pyke 1968, Jenner 1973, Tannahill 1973, NRC 1975). Although practical experience has taught us to avoid certain plants or animals because eating them results in illness, that experience is limited, largely anecdotal, and incomplete. We usually avoid acute toxicants—those things that make us unpleasantly sick immediately. However, we rarely possess sufficient knowledge about foods that contain naturally occurring toxicants that could cause delayed or chronic effects, including cancer.
In contrast, there are many potentially useful foods we avoid or disregard for reasons of unawareness, aesthetics, religion, culture, or cost. All human diets that sustain life and normal activity must supply at least the minimum quantity of the essential nutrients, including calories. Even given differences in age, body weight, and activity level, the range of those requirements for children and adults is fairly narrow—less than threefold. The range of variation in the foods that supply those nutrients, however, is enormous. Contrast the traditional Eskimo diet, high in animal fat and protein, with the vegetarian diet of the Seventh-Day Adventist or Hindu. Many diets in developing countries are low in animal protein simply because it is too expensive or unavailable. The use of spices and seasonings is often a distinctive cultural mark (Rozin 1973). The foods we choose to eat are merely a fraction of those we could eat. Furthermore, many dietary patterns shift over time, as demonstrated by our current—but recent—broad North American fondness for traditional Italian, Asian, and Latin American foods.
The variety in our modern food supply is due largely to the many

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different species of plants we consume. There are estimated to be about 250,000 species of flowering plants, and at least 11,000 are used as foods, spices, or flavoring agents (Tanaka 1976), including vegetables, fruits, and nuts. In some cases, different parts of the same plant are used as food, such as celery stalks, celery seeds, and celery essential oil (derived from the seed). The constituents of each plant part, and hence the expected biological activities, may be entirely different.
The Major Components
In biochemistry and nutrition, it is customary to think of food in terms of its major components. Across the entire U.S. food supply (plant, animal, and microbial), these component classes are, in descending order of concentration, water, carbohydrate, fat, protein, the non-nutrients, and the micronutrients, including minerals and vitamins. On average, carbohydrates supply 46% of our calories, fats supply 42%, and proteins supply 12% (Whistler and Daniel 1985). Of these component classes, proteins are the only primary gene products, i.e., the only class of components (other than DNA and the RNAs) produced directly by the operation of the genetic code of the organism. Minerals are absorbed from the environment, including the diet. All the other component classes are secondary gene products, produced in each organism by the action of the primary gene products, the proteins.
Carbohydrates consist of single or polymerized multiple units of simple sugars, such as glucose or fructose. Glucose, by itself, occurs naturally in foods only to a very limited extent; however, it is the most abundant sugar in the world. Combined chemically with other simple sugars in disaccharides such as sucrose and in starch, a polysaccharide composed solely of glucose, it constitutes about three-fourths of total dietary carbohydrates (Whistler and Daniel 1985). In the American diet, sucrose, fructose, and glucose supply

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more than half of carbohydrate calories and starch the remainder. The overall structure of nearly all dietary carbohydrates is remarkably similar—simple sugars in their ring (hemiacetal pyranose) form, linked together in chains. The large differences in their digestibility and functional characteristics lie in the length of these chains, the degree of branching, and in more subtle aspects of structure.
Lipids are a broad group of naturally occurring compounds that typically are freely soluble in organic solvents and nearly insoluble in water. The glycerol esters of fatty acids (triacyl glycerols, also called triglycerides) form up to 99% of the lipids of plant and animal origin and are customarily called fats, or somewhat more precisely, fats and oils (Hawk 1965; Anonymous 1970, 1986; Nawar 1985; NRC 1989b). Fats is the more specific term for those that are solid or semisolid at room temperature and are typically of animal origin, e.g., lard and butter. Oils, such as soy, olive, and corn oils, are liquid at room temperature and are usually of plant origin, although these distinctions have exceptions, e.g., whale oil. Those lipids that are not triacyl glycerols are quantitatively minor but of enormous physiological importance. They include cholesterol, the phospholipids in cell membranes, prostaglandins, and a host of other substances of structural and functional significance (Stryer 1975). Although all triacyl glycerols share the same basic structure, the differences in melting point, oxidative stability, nutritional qualities, and other important characteristics depend on structural aspects, such as fatty acid chain length and degree of unsaturation.
The basic structure of all proteins is that of a polypeptide—a polymer of -aminocarboxylic acids linked by amide bonds. In terminology parallel to that used for the carbohydrates, two amino acids form a dipeptide, and three form a tripeptide. Peptides containing more than three, but fewer than ten amino acids, are often called oligopeptides, and those with ten or more are polypeptides. More than 400 different amino acids occur in nature (Harborne 1993), but only 20 are found in the major food proteins. Of these,

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nine are essential in human diets. As will be discussed later, proteins serve several diverse and essential purposes in the organisms that produce them. Although all are polypeptides, the number and sequence of the different amino acids, the nature of the chain—linear, branched, or ring, the additional functional groups (e.g., amino or carboxylic acid) on certain amino acids, and the three-dimensional conformation of the entire molecule determine the physiological role of each protein (Cheftel et al. 1985).
Alcohol, a nutrient only in the sense of a source of calories, is discussed in the section on ''Identifying Potential Human Dietary Carcinogens."
The Minor Components
Minor components of food include the micronutrients (minerals and vitamins), the enzymes that all organisms produce and use as essential catalysts for their own life processes, and the DNA and RNAs that determine the nature of all constituents. In addition, plants and animals, and therefore foods derived from both, contain an almost unlimited variety of largely non-nutrient organic compounds often termed natural products or secondary metabolites. In this report, natural products or secondary metabolites are categorized as constitutive naturally occurring chemicals. Although chemically quite distinct, these chemicals are formed by modification of the same building blocks and biosynthetic pathways that produce carbohydrates, fats, and proteins. Examples of these chemicals are volatile oils, waxes, pigments, alkaloids, sterols, flavonoids, toxins, and hormones. Most plants contain one or a few minor constitutive naturally occurring chemicals of toxicologic or pharmacologic interest. This report intentionally focuses on the minority of these chemicals that are known or are suspected to cause, enhance, or inhibit cancer in humans. However, because of inherent low toxicity or low concentration, the vast majority of these naturally

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occurring chemicals are known or can reasonably be presumed not to pose a toxic threat.
Within the higher plants—excluding animals, fungi, and microorganisms—the enormous complexity arises from variations on only a few major biosynthetic pathways, all of which use as their starting materials compounds derived from carbohydrates produced by photosynthesis. In addition to photosynthesis, the principal pathways are
The shikimic acid pathway, which produces compounds containing benzene rings and related structures (including the three aromatic amino acids—phenylalanine, tyrosine, and tryptophan and a host of secondary metabolites derived from them—numerous quinones, benzoic acid derivatives, lignin, and many other benzenoid compounds)
The acetate (polyketide) pathway, which adds two carbon atoms at a time and is responsible for fats, waxes, hydrocarbons, certain phenols, and for portions of the structures of many minor constituents
The isoprenoid pathway, which combines 5-carbon isoprene units (derived from acetate) and is the source of terpenes (e.g., volatile flavor compounds such as menthol and camphor), plant pigments (e.g., carotenes, including Vitamin A), sterols, and rubber
Protein synthesis, which combines amino acids to produce the primary gene products, proteins, including enzymes
Still further complexity is found in products such as alkaloids that arise from combinations of these pathways.
Complexity and Variability
The identity of the specific constituents in the minor and major components of food—the qualitative composition—is in large part

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determined genetically. Environmental factors also affect qualitative composition and influence quantitative composition. Any particular crop is the result of the interplay of genetics and environment. Thus the genetic promise inherent in highly productive and disease-resistant new varieties of rice and wheat—the "green revolution"—cannot be realized without more intensive and better controlled cultural practices, including fertilization and irrigation. For plants, the relevant environmental factors include
Latitude, which determines hours of daylight
Climate (long-term temperature and rainfall trends)
Weather (short-term temperature and rainfall)
Altitude, which affects temperature independently of latitude, climate, and weather
Agricultural practices, such as fertilization and irrigation
Maturity at harvest
Post-harvest processing
Soil conditions (e.g., selenium content)
Storage conditions
For foods of animal origin, the factors are diet, geographic origin, animal husbandry practices, season of harvest or slaughter, and environmental conditions prior to and at harvest or slaughter. All such factors have a major influence on the chemical composition of foods consumed in the diet.
Because of genetic and environmental factors, variation in the quantitative composition of individual foods is often great and can be dramatic. The usual food composition tables provide a useful overall picture, but the average values they contain give little indication of this variation.
Of the major components, water, carbohydrate, and protein vary the least and are typically, though not always, within 20% of the average value. Fat content varies somewhat more, from 50 to 200% of the average value, in foods of both vegetable and animal origin.

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This greater variation in fat content reflects genetic and cultural practices, ones that are now changing because of recent appreciation of the role nutrition plays in chronic disease. Trace nutrients, constitutive naturally occurring chemicals, and natural contaminants are subject to much wider variation in foods derived from plants. Table 2-1 presents data representative of these variations in the U.S. diet.
Some foods, e.g., paprika, demonstrate inherently great variability in composition, reflecting variation in plant strain, climate, geographical source, and post-harvest processing. Some constituents, e.g., vitamin C, are highly variable in most of their dietary sources and for the same reasons. When these factors combine, the variability can be extreme: note, for example, the ascorbic acid content of paprika, for which the standard deviation (SD) is nearly equal to the mean. Standard deviations that are large compared with the mean imply that circumstances have combined and led to high production of that particular constituent. In general, variation is greater, i.e., the SD is larger relative to the mean, for
Plant foods rather than animal foods (animal foods are usually subject to greater genetic control and less environmental influence with the exception of fat content)
Microconstituents (those present at less than 1%), as opposed to macroconstitutents (those present at more than 1%)
Plant foods that have a broad genetic base and are produced in many areas (e.g., paprika), as opposed to those that have a narrower genetic base and are produced in a few areas (e.g., California Valencia oranges).
Microconstituents such as selenium vary even more dramatically than those shown in Table 2-1, because of the great variation in the selenium content of soils.
Although the minor constituents account for only small percentages of total composition by weight, they are by far the largest number